Chemokines have been classified into four groups according to their structures. CXC and CC chemokines, the two large groups, feature the presence and absence of an amino acid, respectively, between the first two cysteine residues in a conserved four-cysteine motif (Mackay C. R., Nat. Immunol., (2001) 2:95; Olson et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., (2002) 283:R7). CXCR3 is the first chemokine receptor found to be highly induced by T cell activation (Loetscher et al., J. Exp. Med., (1996) 184:963). CXCR3 is expressed on some circulating blood T cells, B cells, and natural killer cells (Qin et al., J. Clin. Invest., (1998) 101:746). For example, expression of CXCR3 is induced virtually by all T cells in synovial fluid of rheumatoid arthritis and in various inflamed tissues (e.g., ulcerative colitis, chronic vaginitis, and sarcoidosis), particularly in perivascular regions. However, few T cells in normal lymph nodes are induced to express CXCR3 (Agostini et al., J. Immunol., (1998) 161:6413). Expression and responsiveness of CXCR3 can be markedly increased by T cell activation (Rabin et al., J. Immunol., (1999) 162:3840). CXCR3 is also consistently detected in functional forms on transformed B cells obtained from chronic lymphocytic leukemia patients (Trentin et al., J. Clin. Invest., (1999) 104:115).
CXCR3 binds to three highly potent, inflammation-inducible, ELR-negative CXC chemokines, i.e., I-TAC, Mig, and IP-10. These three chemokines chemoattract and induce calcium influx in activated T cells, tumor-infiltrating lymphocytes, and CXCR3-transfected cells (Loetscher et al., Eur. J. Immunol., (1998) 28:3696; Cole et al., J. Exp. Med., (1998) 187:2009; Weng et al., J. Biol. Chem., (1998) 273:18288). CXCR3 signaling appears to be an important mechanism for selective homing of activated/effector cells, which are known to accumulate preferentially at inflammatory sites and in many tumors. For example, IP-10 is expressed abundantly at various inflammatory sites, particularly those characterized by T cell infiltration, such as in tissues affected by delayed type hypersensitivity responses, experimental autoimmune encephalomyelitis, or a transplant undergoing rejection (Qin et al., J. Clin. Invest., (1998) 101:746). CXCR3 ligand-induced recruitment of leukocytes is thought to be an essential step in the pathogenesis of tissue-specific autoimmune inflammatory diseases, as well as in graft rejection (Hancock et al., J. Exp. Med., (2000) 192:1515).